DNA or RNA delivery to a target cell mediated by a nonviral synthetic vector (lipoplex and polyplex) has been widely recognized as a promising alternative method for delivery that uses a viral vector which has been confronting safety issues specific to biological properties[1]. Nonetheless, even in the case of a nonviral vector, the main concern is the conflict between the delivery efficiency and the safety issues (in particular, chemical toxicity). While most vectors having high transfection efficiency show high toxicity, vectors with low toxicity are often associated with low transfection efficiency. Behr et al. introduced a concept of endosomal escape through “proton-sponge” effect, a hypothesis proposed for polyethylenimine (PEI), into the field of gene delivery. Since then, various basicity-adjusted polycations have been developed for construction of polyplexes. However, due to the toxicity of these polycations, polyplexes are used only for limited applications[2]. One major reason for limited development of polycation is presumably that different functions, which may be opposing functions, of the polyplex are required at different stages of the delivery process. For example, a moiety having a high amine density in a polyplex is important to overcome the endosomal membrane barrier since a protonated potential of the polyplex could be a cause of endosome buffering and membrane destabilization[3]. On the contrary, the positively-charged property of a polyplex could cause non-specific interaction with a negatively-charged serum component, thereby producing a thrombus in the blood capillary. This has a risk of disturbing construction of a plasma membrane and a risk of inducing high cytotoxicity and excess immune response[4]. An example of well known practical solutions to these problems is positive charge shielding by covering the surface of the polyplex with polyanion[5] or polyethylene glycol (PEG)[6]. In this case, however, severe loss in transfection efficiency cannot be avoided primarily due to decrease in the cellular uptake and deterioration of the endosomal escape ability.
Thus, efforts have been focused on the development of a deshielding method at a certain point during the transfection process[7].